Thalamic circuits for independent control of prefrontal signal and noise.

Interactions between the mediodorsal thalamus and the prefrontal cortex are critical for cognition. Studies in humans indicate that these interactions may resolve uncertainty in decision-making1, but the precise mechanisms are unknown. Here we identify two distinct mediodorsal projections to the prefrontal cortex that have complementary mechanistic roles in decision-making under uncertainty. Specifically, we found that a dopamine receptor (D2)-expressing projection amplifies prefrontal signals when task inputs are sparse and a kainate receptor (GRIK4) expressing-projection suppresses prefrontal noise when task inputs are dense but conflicting. Collectively, our data suggest that there are distinct brain mechanisms for handling uncertainty due to low signals versus uncertainty due to high noise, and provide a mechanistic entry point for correcting decision-making abnormalities in disorders that have a prominent prefrontal component2-6.

Neural circuits underlying a psychotherapeutic regimen for fear disorders.

A psychotherapeutic regimen that uses alternating bilateral sensory stimulation (ABS) has been used to treat post-traumatic stress disorder. However, the neural basis that underlies the long-lasting effect of this treatment-described as eye movement desensitization and reprocessing-has not been identified. Here we describe a neuronal pathway driven by the superior colliculus (SC) that mediates persistent attenuation of fear. We successfully induced a lasting reduction in fear in mice by pairing visual ABS with conditioned stimuli during fear extinction. Among the types of visual stimulation tested, ABS provided the strongest fear-reducing effect and yielded sustained increases in the activities of the SC and mediodorsal thalamus (MD). Optogenetic manipulation revealed that the SC-MD circuit was necessary and sufficient to prevent the return of fear. ABS suppressed the activity of fear-encoding cells and stabilized inhibitory neurotransmission in the basolateral amygdala through a feedforward inhibitory circuit from the MD. Together, these results reveal the neural circuit that underlies an effective strategy for sustainably attenuating traumatic memories.

Identifying the pathways required for coping behaviours associated with sustained pain.

Animals and humans display two types of response to noxious stimuli. The first includes reflexive defensive responses that prevent or limit injury; a well-known example of these responses is the quick withdrawal of one's hand upon touching a hot object. When the first-line response fails to prevent tissue damage (for example, a finger is burnt), the resulting pain invokes a second-line coping response-such as licking the injured area to soothe suffering. However, the underlying neural circuits that drive these two strings of behaviour remain poorly understood. Here we show in mice that spinal neurons marked by coexpression of TAC1Cre and LBX1Flpo drive coping responses associated with pain. Ablation of these spinal neurons led to the loss of both persistent licking and conditioned aversion evoked by stimuli (including skin pinching and burn injury) that-in humans-produce sustained pain, without affecting any of the reflexive defensive reactions that we tested. This selective indifference to sustained pain resembles the phenotype seen in humans with lesions of medial thalamic nuclei1-3. Consistently, spinal TAC1-lineage neurons are connected to medial thalamic nuclei by direct projections and via indirect routes through the superior lateral parabrachial nuclei. Furthermore, the anatomical and functional segregation observed at the spinal level also applies to primary sensory neurons. For example, in response to noxious mechanical stimuli, MRGPRD- and TRPV1-positive nociceptors are required to elicit reflexive and coping responses, respectively. Our study therefore reveals a fundamental subdivision within the cutaneous somatosensory system, and challenges the validity of using reflexive defensive responses to measure sustained pain.

Two contrasting mediodorsal thalamic circuits target the mouse medial prefrontal cortex.

At the heart of the prefrontal network is the mediodorsal (MD) thalamus. Despite the importance of MD in a broad range of behaviors and neuropsychiatric disorders, little is known about the physiology of neurons in MD. We injected the retrograde tracer cholera toxin subunit B (CTB) into the medial prefrontal cortex (mPFC) of adult wild-type mice. We prepared acute brain slices and used current clamp electrophysiology to measure and compare the intrinsic properties of the neurons in MD that project to mPFC (MD→mPFC neurons). We show that MD→mPFC neurons are located predominantly in the medial (MD-M) and lateral (MD-L) subnuclei of MD. MD-L→mPFC neurons had shorter membrane time constants and lower membrane resistance than MD-M→mPFC neurons. Relatively increased hyperpolarization-activated cyclic nucleotide-gated (HCN) channel activity in MD-L neurons accounted for the difference in membrane resistance. MD-L neurons had a higher rheobase that resulted in less readily generated action potentials compared with MD-M→mPFC neurons. In both cell types, HCN channels supported generation of burst spiking. Increased HCN channel activity in MD-L neurons results in larger after-hyperpolarization potentials compared with MD-M neurons. These data demonstrate that the two populations of MD→mPFC neurons have divergent physiologies and support a differential role in thalamocortical information processing and potentially behavior.NEW & NOTEWORTHY To realize the potential of circuit-based therapies for psychiatric disorders that localize to the prefrontal network, we need to understand the properties of the populations of neurons that make up this network. The mediodorsal (MD) thalamus has garnered attention for its roles in executive functioning and social/emotional behaviors mediated, at least in part, by its projections to the medial prefrontal cortex (mPFC). Here, we identify and compare the physiology of the projection neurons in the two MD subnuclei that provide ascending inputs to mPFC in mice. Differences in intrinsic excitability between the two populations of neurons suggest that neuromodulation strategies targeting the prefrontal thalamocortical network will have differential effects on these two streams of thalamic input to mPFC.

Electrophysiological and morphological properties of prefrontal pyramidal neurons innervated by mediodorsal thalamus.

The high-order cognitive and executive functions are necessary for an individual to survive. The densely bidirectional innervations between the medial prefrontal cortex (mPFC) and the mediodorsal thalamus (MD) play a vital role in regulating high-order functions. Pyramidal neurons in mPFC have been classified into several subclasses according to their morphological and electrophysiological properties, but the properties of the input-specific pyramidal neurons in mPFC remain poorly understood. The present study aimed to profile the morphological and electrophysiological properties of mPFC pyramidal neurons innervated by MD. In the past, the studies for characterizing the morphological and electrophysiological properties of neurons mainly relied on the electrophysiological recording of a large number of neurons and their morphologic reconstructions. But, it is a low efficient method for characterizing the circuit-specific neurons. The present study combined the advantages of traditional morphological and electrophysiological methods with machine learning to address the shortcomings of the past method, to establish a classification model for the morphological and electrophysiological properties of mPFC pyramidal neurons, and to achieve more accurate and efficient identification of the properties from a small size sample of neurons. We labeled MD-innervated pyramidal neurons of mPFC using the trans-synaptic neural circuitry tracing method and obtained their morphological properties using whole-cell patch-clamp recording and morphologic reconstructions. The results showed that the classification model established in the present study could predict the electrophysiological properties of MD-innervated pyramidal neurons based on their morphology. MD-innervated pyramidal neurons exhibit larger basal dendritic length but lower apical dendrite complexity compared to non-MD-innervated neurons in the mPFC. The morphological characteristics of the two subtypes (ET-1 and ET-2) of mPFC pyramidal neurons innervated by MD are different, with the apical dendrites of ET-1 neurons being longer and more complex than those of ET-2 neurons. These results suggest that the electrophysiological properties of MD- innervated pyramidal neurons within mPFC correlate with their morphological properties, indicating that the different roles of these two subclasses in local circuits within PFC, as well as in PFC-cortical/subcortical brain region circuits.

Organization of primate amygdalar-thalamic pathways for emotions.

Studies on the thalamus have mostly focused on sensory relay nuclei, but the organization of pathways associated with emotions is not well understood. We addressed this issue by testing the hypothesis that the primate amygdala acts, in part, like a sensory structure for the affective import of stimuli and conveys this information to the mediodorsal thalamic nucleus, magnocellular part (MDmc). We found that primate sensory cortices innervate amygdalar sites that project to the MDmc, which projects to the orbitofrontal cortex. As in sensory thalamic systems, large amygdalar terminals innervated excitatory relay and inhibitory neurons in the MDmc that facilitate faithful transmission to the cortex. The amygdala, however, uniquely innervated a few MDmc neurons by surrounding and isolating large segments of their proximal dendrites, as revealed by three-dimensional high-resolution reconstruction. Physiologic studies have shown that large axon terminals are found in pathways issued from motor systems that innervate other brain centers to help distinguish self-initiated from other movements. By analogy, the amygdalar pathway to the MDmc may convey signals forwarded to the orbitofrontal cortex to monitor and update the status of the environment in processes deranged in schizophrenia, resulting in attribution of thoughts and actions to external sources.

Regional Specialization of Pyramidal Neuron Morphology and Physiology in the Tree Shrew Neocortex.

The mammalian cerebral cortex is divided into different areas according to their function and pattern of connections. Studies comparing primary visual (V1) and prefrontal cortex (PFC) of primates have demonstrated striking pyramidal neuron (PN) specialization not present in comparable areas of the mouse neocortex. To better understand PFC evolution and regional PN specialization, we studied the tree shrew, a species with a close phylogenetic relationship to primates. We defined the tree shrew PFC based on cytoarchitectonic borders, thalamic connectivity and characterized the morphology and electrophysiology of layer II/III PNs in V1 and PFC. Similar to primates, the PFC PNs in the tree shrew fire with a regular spiking pattern and have larger dendritic tree and spines than those in V1. However, V1 PNs showed strikingly large basal dendritic arbors with high spine density, firing at higher rates and in a more varied pattern than PFC PNs. Yet, unlike in the mouse and unreported in the primate, medial prefrontal PN are more easily recruited than either the dorsolateral or V1 neurons. This specialization of PN morphology and physiology is likely to be a significant factor in the evolution of cortex, contributing to differences in the computational capacities of individual cortical areas.

Low levels of muscarinic M1 receptor-positive neurons in cortical layers III and V in Brodmann areas 9 and 17 from individuals with schizophrenia.

BACKGROUND: Results of neuroimaging and postmortem studies suggest that people with schizophrenia may have lower levels of muscarinic M1 receptors (CHRM1) in the cortex, but not in the hippocampus or thalamus. Here, we use a novel immunohistochemical approach to better understand the likely cause of these low receptor levels. METHODS: We determined the distribution and number of CHRM1-positive (CHRM1+) neurons in the cortex, medial dorsal nucleus of the thalamus and regions of the hippocampus from controls (n = 12, 12 and 5, respectively) and people with schizophrenia (n = 24, 24 and 13, respectively). RESULTS: Compared with controls, levels of CHRM1+ neurons in people with schizophrenia were lower on pyramidal cells in layer III of Brodmann areas 9 (-44%) and 17 (-45%), and in layer V in Brodmann areas 9 (-45%) and 17 (-62%). We found no significant differences in the number of CHRM1+ neurons in the medial dorsal nucleus of the thalamus or in the hippocampus. LIMITATIONS: Although diagnostic cohort sizes were typical for this type of study, they were relatively small. As well, people with schizophrenia were treated with antipsychotic drugs before death. CONCLUSION: The loss of CHRM1+ pyramidal cells in the cortex of people with schizophrenia may underpin derangements in the cholinergic regulation of GABAergic activity in cortical layer III and in cortical/subcortical communication via pyramidal cells in layer V.

Electroresponsive properties of rat central medial thalamic neurons.

The central medial thalamic (CMT) nucleus is a poorly known component of the middle thalamic complex that relays nociceptive inputs to the basolateral amygdala and cingulate cortex and plays a critical role in the control of awareness. The present study was undertaken to characterize the electroresponsive properties of CMT neurons. Similar to relay neurons found throughout the dorsal thalamus, CMT cells assumed tonic or burst-firing modes, depending on their membrane potentials (Vm). However, they showed little evidence of the hyperpolarization-activated mixed cationic conductance (IH)-mediated inward rectification usually displayed by dorsal thalamic relay cells at hyperpolarized Vm Two subtypes of CMT neurons were identified when comparing their responses with depolarization applied from negative potentials. Some cells generated a low-threshold spike burst followed by tonic firing, whereas others remained silent after the initial burst, irrespective of the amount of depolarizing current injected. Equal proportions of the two cell types were found among neurons retrogradely labeled from the basolateral amygdala. Their morphological properties were heterogeneous but distinct from the classical bushy relay cell type that prevails in most of the dorsal thalamus. We propose that the marginal influence of IHin CMT relative to other dorsal thalamic nuclei has significant network-level consequences. Because IHpromotes the genesis of highly coherent delta oscillations in thalamocortical networks during sleep, these oscillations may be weaker or less coherent in CMT. Consequently, delta oscillations would be more easily disrupted by peripheral inputs, providing a potential mechanism for the reported role of CMT in eliciting arousal from sleep or anesthesia.

Motor afferents from the cerebellum, zona incerta and substantia nigra to the mediodorsal thalamic nucleus in the rat.

The mediodorsal (MD) thalamic nucleus provides information from subcortical structures to the prefrontal cortex. The human MD thalamic nucleus has been implicated in a great variety of different clinical conditions and normal functions ranging from schizophrenia, Parkinsonism and epilepsy to many cognitive functions. In the rat the MD thalamic nucleus is divided into three cytoarchitectonic sectors whereas in the primates it is divided into two; medial one-third (magnocellular) and lateral two-thirds further the lateral sector is divided into pars parvocellularis pars multiformis, pars fasciculosa and pars caudalis. In this study we used a retrograde tracer, fluoro-gold (FG) to evaluate some of the afferents reaching the lateral sector of the MD (MDl) thalamic nucleus. The results of the present study have shown that MDl receives afferent connections from the lateral cerebellar nucleus (dentate nucleus), substantia nigra pars reticulata (SNR) and zona incerta (ZI). Subsequent to FG injections into the MDl, labeled cells were observed mainly bilaterally but were sparser on the contralateral side than ipsilaterally from each of the three structures listed. All three afferents showed a topographical organization. The labeled neurons were localized at the dorsomedial aspect of the lateral cerebellar nucleus, the dorsoventral aspect of the SNR and in the dorsal sector of the ZI. The lateral cerebellar nucleus reached the MDl via the superior cerebellar peduncle. No other deep cerebellar nuclei showed labeled cells. There were no labeled cells in the substantia nigra pars compacta (SNC). Although the three regions identified here are recognized as having motor functions, the connections to MD suggest that their outputs also play a role in cognitive or other higher cortical functions.

Pathways for emotions and attention converge on the thalamic reticular nucleus in primates.

How do emotional events readily capture our attention? To address this question we used neural tracers to label pathways linking areas involved in emotional and attentional processes in the primate brain (Macaca mulatta). We report that a novel pathway from the amygdala, the brain's emotional center, targets the inhibitory thalamic reticular nucleus (TRN), a key node in the brain's attentional network. The amygdalar pathway formed unusual synapses close to cell bodies of TRN neurons and had more large and efficient terminals than pathways from the orbitofrontal cortex and the thalamic mediodorsal nucleus, which similarly innervated extensive TRN sites. The robust amygdalar pathway provides a mechanism for rapid shifting of attention to emotional stimuli. Acting synergistically, pathways from the amygdala and orbitofrontal cortex provide a circuit for purposeful assessment of emotional stimuli. The different pathways to TRN suggest distinct mechanisms of attention to external and internal stimuli that may be differentially disrupted in anxiety and mood disorders and may be selectively targeted for therapeutic interventions.

Regional connections of the mediodorsal thalamic nucleus in the rat.

Thalamic nuclei are classified as first- and higher-order relays. The first-order relays receive their driving afferents from ascending pathways and transmit messages to cortex that cortex has not seen before. The higher-order relays receive driver messages from layer-5 cortical cells for transmission from one cortical area to another. The present study used the retrograde tracer, fluoro-gold, to define the afferents to the three regions of the mediodorsal thalamic nucleus, to distinguish which parts contain first- or higher-order relays. The results show that the main inputs to the medial region of the nucleus come from olfactory and visceral structures, those to the central region come from limbic structures and those to the lateral region come from motor centers of the central nervous system. The medial and central regions receive both modulatory (layer 6) and driver (layer 5) afferent inputs from the orbitofrontal and medial frontal areas of the prefrontal cortex whereas the lateral region receives no layer-5 inputs from its cortical connections. Further, the inhibitory modulation of the mediodorsal thalamic nucleus shows regional differences. The medial region receives inhibitory afferents from the striatum (globus pallidus, caudate-putamen), the lateral region from the substantia nigra pars reticulata and the zona incerta, and all segments of the mediodorsal thalamic nucleus receive inhibitory afferents from the thalamic reticular nucleus. The results of the present study show that each region of the mediodorsal thalamic nucleus has distinct afferent connections allowing each region of mediodorsal thalamic nucleus to be considered relatively independent subnuclei that may subserve independent functions.

Olfaction in Lamprey Pallium Revisited-Dual Projections of Mitral and Tufted Cells.

The presence of two separate afferent channels from the olfactory glomeruli to different targets in the brain is unravelled in the lamprey. The mitral-like cells send axonal projections directly to the piriform cortex in the ventral part of pallium, whereas the smaller tufted-like cells project separately and exclusively to a relay nucleus called the dorsomedial telencephalic nucleus (dmtn). This nucleus, located at the interface between the olfactory bulb and pallium, in turn projects to a circumscribed area in the anteromedial, ventral part of pallium. The tufted-like cells are activated with short latency from the olfactory nerve and terminate with mossy fibers on the dmtn cells, wherein they elicit large unitary excitatory postsynaptic potentials (EPSPs). In all synapses along this tufted-like cell pathway, there is no concurrent inhibition, in contrast to the mitral-like cell pathway. This is similar to recent findings in rodents establishing two separate exclusive projection patterns, suggesting an evolutionarily conserved organization.

Mediodorsal and Ventromedial Thalamus Engage Distinct L1 Circuits in the Prefrontal Cortex.

Interactions between the thalamus and prefrontal cortex (PFC) play a critical role in cognitive function and arousal. Here, we use anatomical tracing, electrophysiology, optogenetics, and 2-photon Ca2+ imaging to determine how ventromedial (VM) and mediodorsal (MD) thalamus target specific cell types and subcellular compartments in layer 1 (L1) of mouse PFC. We find thalamic inputs make distinct connections in L1, where VM engages neuron-derived neurotrophic factor (NDNF+) cells in L1a and MD drives vasoactive intestinal peptide (VIP+) cells in L1b. These separate populations of L1 interneurons participate in different inhibitory networks in superficial layers by targeting either parvalbumin (PV+) or somatostatin (SOM+) interneurons. NDNF+ cells also inhibit the apical dendrites of L5 pyramidal tract (PT) cells to suppress action potential (AP)-evoked Ca2+ signals. Lastly, NDNF+ cells mediate a unique form of thalamus-evoked inhibition at PT cells, selectively blocking VM-evoked dendritic Ca2+ spikes. Together, our findings reveal how two thalamic nuclei differentially communicate with the PFC through distinct L1 micro-circuits.

Dopamine innervation in the thalamus: monkey versus rat.

We recently identified the thalamic dopaminergic system in the human and macaque monkey brains, and, based on earlier reports on the paucity of dopamine in the rat thalamus, hypothesized that this dopaminergic system was particularly developed in primates. Here we test this hypothesis using immunohistochemistry against the dopamine transporter (DAT) in adult macaque and rat brains. The extent and density of DAT-immunoreactive (-ir) axons were remarkably greater in the macaque dorsal thalamus, where the mediodorsal association nucleus and the ventral motor nuclei held the densest immunolabeling. In contrast, sparse DAT immunolabeling was present in the rat dorsal thalamus; it was mainly located in the mediodorsal, paraventricular, ventral medial, and ventral lateral nuclei. The reticular nucleus, zona incerta, and lateral habenular nucleus held numerous DAT-ir axons in both species. Ultrastructural analysis in the macaque mediodorsal nucleus revealed that thalamic interneurons are a main postsynaptic target of DAT-ir axons; this suggests that the marked expansion of the dopamine innervation in the primate in comparison to the rodent thalamus may be related to the presence of a sizable interneuron population in primates. We remark that it is important to be aware of brain species differences when using animal models of human brain disease.

Schizophrenia; from structure to function with special focus on the mediodorsal thalamic prefrontal loop.

OBJECTIVE: To describe structural and biochemical evidence from postmortem brains that implicates the reciprocal connections between the mediodorsal thalamic nucleus and the prefrontal cortex in cognitive symptoms of schizophrenia. METHOD: The estimation of the regional volumes and cell numbers was obtained using stereological methods. The biochemical analyses of molecular expression in postmortem brain involve quantitative measurement of transcripts and proteins by in-situ (RNA) or Western blot/autoradiography in brains from patients with schizophrenia and comparison subjects. RESULTS: Stereological studies in postmortem brain from patients with schizophrenia have reported divergent and often opposing findings in the total number of neurons and volume of the mediodorsal (MD) thalamic nucleus, and to a lesser degree in its reciprocally associated areas of the prefrontal cortex. Similarly, quantitative molecular postmortem studies have found large inter-subject and between-study variance at both the transcript and protein levels for receptors and their interacting molecules of several neurotransmitter systems in these interconnected anatomical regions. Combined, large variation in stereological and molecular studies indicates a complex and heterogeneous involvement of the MD thalamic-prefrontal loop in schizophrenia. CONCLUSION: Based on a considerable heterogeneity in patients suffering from schizophrenia, large variation in postmortem studies, including stereological and molecular postmortem studies of the MD thalamus and frontal cortex, might be expected and may in fact partly help to explain the variable endophenotypic traits associated with this severe psychiatric illness.

Clozapine Normalizes a Glutamatergic Transmission Abnormality Induced by an Impaired NMDA Receptor in the Thalamocortical Pathway via the Activation of a Group III Metabotropic Glutamate Receptor.

Pharmacological mechanisms of gold-standard antipsychotics against treatment-refractory schizophrenia, such as clozapine (CLZ), remain unclear. We aimed to explore the mechanisms of CLZ by investigating the effects of MK801 and CLZ on tripartite synaptic transmission in the thalamocortical glutamatergic pathway using multi-probe microdialysis and primary cultured astrocytes. l-glutamate release in the medial prefrontal cortex (mPFC) was unaffected by local MK801 administration into mPFC but was enhanced in the mediodorsal thalamic nucleus (MDTN) and reticular thalamic nucleus (RTN) via GABAergic disinhibition in the RTN-MDTN pathway. The local administration of therapeutically relevant concentrations of CLZ into mPFC and MDTN increased and did not affect mPFC l-glutamate release. The local administration of the therapeutically relevant concentration of CLZ into mPFC reduced MK801-induced mPFC l-glutamate release via presynaptic group III metabotropic glutamate receptor (III-mGluR) activation. However, toxic concentrations of CLZ activated l-glutamate release associated with hemichannels. This study demonstrated that RTN is a candidate generator region in which impaired N-methyl-d-aspartate (NMDA)/glutamate receptors likely produce thalamocortical hyperglutamatergic transmission. Additionally, we identified several mechanisms of CLZ relating to its superiority in treatment-resistant schizophrenia and its severe adverse effects: (1) the prevention of thalamocortical hyperglutamatergic transmission via activation of mPFC presynaptic III-mGluR and (2) activation of astroglial l-glutamate release associated with hemichannels. These actions may contribute to the unique clinical profile of CLZ.

Modulation of thalamo-cortical activity by the NMDA receptor antagonists ketamine and phencyclidine in the awake freely-moving rat.

Non-competitive N-methyl-d-aspartate receptor antagonists mimic schizophrenia symptoms and produce immediate and persistent antidepressant effects. We investigated the effects of ketamine and phencyclidine (PCP) on thalamo-cortical network activity in awake, freely-moving male Wistar rats to gain new insight into the neuronal populations and brain circuits involved in the effects of NMDA-R antagonists. Single unit and local field potential (LFP) recordings were conducted in mediodorsal/centromedial thalamus and in medial prefrontal cortex (mPFC) using microelectrode arrays. Ketamine and PCP moderately increased the discharge rates of principal neurons in both areas while not attenuating the discharge of mPFC GABAergic interneurons. They also strongly affected LFP activity, reducing beta power and increasing that of gamma and high-frequency oscillation bands. These effects were short-lasting following the rapid pharmacokinetic profile of the drugs, and consequently were not present at 24 h after ketamine administration. The temporal profile of both drugs was remarkably different, with ketamine effects peaking earlier than PCP effects. Although this study is compatible with the glutamate hypothesis for fast-acting antidepressant action, it does not support a local disinhibition mechanism as the source for the increased pyramidal neuron activity in mPFC. The short-lasting increase in thalamo-cortical activity is likely associated with the rapid psychotomimetic action of both agents but could also be part of a cascade of events ultimately leading to the persistent antidepressant effects of ketamine. Changes in spectral contents of high-frequency bands by the drugs show potential as translational biomarkers for target engagement of NMDA-R modulators.

Reorganization of learning-associated prefrontal synaptic plasticity between the recall of recent and remote fear extinction memory.

We have previously shown that fear extinction is accompanied by an increase of synaptic efficacy in inputs from the ventral hippocampus (vHPC) and mediodorsal thalamus (MD) to the medial prefrontal cortex (mPFC) and that disrupting these changes to mPFC synaptic transmission compromises extinction processes. The aim of this study was to examine whether these extinction-related changes undergo further plasticity as the memory of extinction becomes more remote. Changes in synaptic efficacy in both vHPC-mPFC and MD-mPFC inputs were consequently analyzed when the memory was either 1 d or 7 d old. Increases of synaptic efficacy in the vHPC-mPFC pathway were observed when the memory was 1 d old, but not 7 d after initial extinction. In contrast, potentiation of synaptic efficacy in the MD-mPFC pathway increased over time. In rats that received low-frequency vHPC stimulation immediately after extinction, both vHPC-mPFC and MD-mPFC inputs failed to develop potentiation, and the recall of extinction (both recent and remote memories) was impaired. These findings suggest that post-extinction potentiation in vHPC-mPFC inputs may be necessary for both the recall of recent memory and post-extinction potentiation in the MD-mPFC inputs. This late potentiation process may be required for the recall of remote extinction memory.

Morphology and synaptic organization of non-dopaminergic nigral projections to the medio dorsal thalamic nucleus of the rat, a study by anterograde transport of PHA-L.

BACKGROUND: Mediodorsal (MD) thalamic nucleus, which is considered to take place between extra pyramidal and limbic feedback circuit, receives projective fibers from ventrolateral neurons of reticular part of substantia nigra (SNr). In order to better understand the influence and chemical reaction of these fibers upon MD nucleus, the morphology and synaptology of them were examined in the present study. METHODS: Phaseolous vulgaris-leucoagglutin (PHA-L) was injected into substantia nigra pars reticulate. After 3-4 days, the sections of SNr injection site and MD nucleus were prepared. Then, we examined organization, morphology and, synaptology of PHA-L labeled SNr fibers that go to caudal and lateral part of MD thalamic nucleus. RESULTS: At the electron microscopic level, the SNr terminals made synapses predominantly with the medium to small dendrites and far less frequently with soma and large dendrites. These terminals were packed with polymorphic synaptic vesicles and formed symmetrical synapses; furthermore, it has been already recognized that cortico straital fibers from sensory-motor cortex go to region of the SNr that give rise to the nigrothalamic fibers. CONCLUSION: This data suggest that upon the synaptic organization, morphology and chemical nature of GABAergic, SNr fibers may have different inhibitory influence on MD neurons regulating the thalamic output from MD to cerebral cortex in the control of limbic and extra pyramidal feedback system.